EP1015035B1 - Impfung durch topische verwendung genetischer vektoren - Google Patents

Impfung durch topische verwendung genetischer vektoren Download PDF

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Publication number
EP1015035B1
EP1015035B1 EP98939363A EP98939363A EP1015035B1 EP 1015035 B1 EP1015035 B1 EP 1015035B1 EP 98939363 A EP98939363 A EP 98939363A EP 98939363 A EP98939363 A EP 98939363A EP 1015035 B1 EP1015035 B1 EP 1015035B1
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Prior art keywords
skin
gene
adenovirus
dna
vector
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Expired - Lifetime
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EP98939363A
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English (en)
French (fr)
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EP1015035A4 (de
EP1015035A1 (de
Inventor
De-Chu Christopher Tang
Donald H. Marks
David T. Curiel
Zhongkai Shi
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UAB Research Foundation
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UAB Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • the transgene encodes an antigen.
  • An adenovirus recombinant is constructed by cloning specific transgenes or fragments of transgenes into any of the adenovirus vectors such as those described above.
  • the adenovirus recombinant is used to transduce epidermal cells of a vertebrate in a non-invasive mode for use as an immunizing agent.
  • DNA/adenovirus complexes were prepared by mixing 100 ⁇ g plasmid DNA with 1x10 11 particles of adenovirus in the presence of the condensing agent polylysine for each application.
  • the titer of adenovirus was determined by absorbance.
  • Sera from tail bleeds were diluted 1:250 to 1:500 and reacted with purified proteins that had been separated in a SDS-polyacrylamide gel and transferred to an Immobilon-P membrane (Millipore). Reaction was visualized using the ECL kit (Amersham).
  • adenovirus-mediated NIVS is capable of eliciting a humoral immune response against an antigen encoded by the vector.
  • syngeneic tumor cells that express the human carcinoembryonic antigen (CEA) gene (MC38-CEA-2) (Conry et al., 1995) were inoculated into naive C57BL/6 strain mice and the same strain mice that had been vaccinated by topical application of an adenovirus vector encoding the human CEA gene (AdCMV-hcea). Animals subjected to tumor challenges were observed for survival ( Figure 4 ). In the control group, 90% (9/10) of the animals developed palpable tumor nodules and died within 30 days after tumor cell implantation.
  • CEA carcinoembryonic antigen
  • AdCMV-mB7.1 was characterized by staining transduced human lung carcinoma SCC-5 cells with the anti-CD80 antibody (PharMingen), followed by flow cytometric analysis.
  • AdCMV-mgmcsf was characterized by measuring murine GM-CSF secreted from transduced SCC-5 cells with an ELISA kit (Amersham).
  • An in vivo cytotoxicity assay was developed in which target cells were implanted as monolayers onto the muscle tissue of mice (Tang et al., 1996). Implantation of target cells as monolayers allowed for an efficient retrieval of target cells for assessing their fates after a few days of in vivo growth. This assay was particularly useful for detecting weak immune responses that are not potent enough for eradicating target cells. Immune responses can be characterized by histological analysis of the implantation bed. Without an immune response, target cells would grow. With a potent immune response, target cells would be eradicated in the presence of a large number of immune effector cells at the implantation bed, probably by virtue of migration to and in situ sensitization around growing target cells.
  • CTLs that express granzyme A are activated CTLs and have been used as predictive markers for tissue rejection during transplantation.
  • Granzyme-positive CTLs were found within the RM1-luc implantation bed only in animals that had been vaccinated by skin-targeted non-invasive delivery of AdCMV-luc ( Figure 6 ). Their presence at the bed suggests that a cell-mediated immune response against tumor cells expressing a specific antigen may have been induced by NIVS.
  • bandages could be used for the administration of vaccines. This development may allow personnel without medical training to deliver a uniform dose of non-invasive vaccines onto the skin.
  • 50 ⁇ l of the AdCMV-luc vector described in Example 7 was pipetted into the pad of an adhesive bandage (Johnson & Johnson).
  • the vector-containing bandage was subsequently adhered to pre-shaved skin of a mouse.
  • the vector was kept in contact with naked skin for 18 hours.
  • To detect transgene expression from genetic vectors delivered by a bandage the skin was assayed for luciferase (Table 1). While the results show substantial variation, transgene expression in the skin was achievable using adhesive bandages.
  • Adenovirus-based vectors can be made more versatile by binding plasmid DNA to the exterior of an adenovirus.
  • the resulting vector system mediates high-efficiency gene delivery to a wide variety of target cells. This approach allows greatly enhanced flexibility in terms of the size and design of foreign genes.
  • DNA/adenovirus complexes may thus be able to deliver antigen genes into the skin via the same adenovirus receptor-mediated endocytosis pathway with more flexibility.
  • mice could be vaccinated by topical application of DNA/liposome complexes without viral elements. It is apparent that many different vectors can be applied in a creative way for the administration of skin-targeted non-invasive vaccines. As shown in Figure 8b , lane 1, hGH (0.5 ⁇ g); lane 2, BSA (0.5 ⁇ g), the test serum from a mouse immunized by topical application of DNA/liposome complexes encoding hGH reacted with hGH but not with BSA.
  • Adenovirus vectors encoding the murine B7-1 and GM-CSF genes have been made. Topical application of DNA/adenovirus complexes may thus be able to co-express DNA-encoded antigens or immune modulatory molecules with adenovirus-encoded antigens or immune modulatory molecules in individual skin cells for enhancing the immune response against the antigen.
  • Figure 9 shows that the expression of transgenes from plasmid DNA in target cells is dependent upon the presence of adenovirus, thus allowing plasmid-encoded and adenovirus-encoded transgenes to be co-expressed in the same cell.
  • pVR-1216 plasmid DNA (provided by Vical), AdCMV- ⁇ gal particles and polylysine were mixed at specific ratios as shown in the figure.
  • the complex was applied to 2 X 10 5 SCC-5 cells in a well and incubated for 2 hours. The complex was then removed and cells were harvested for luciferase and ⁇ -galactosidase assays the next day.
  • adenovirus recombinants DNA/adenovirus complexes, DNA/liposome complexes, and perhaps many other genetic vectors can all be applied as carriers for non-invasive vaccines. It is conceivable that the higher the efficiency for transgene expression, the more powerful the carrier will be. To define the relative efficiencies for the vectors utilized, adenovirus recombinants, DNA/adenovirus complexes, or DNA/liposome complexes were allowed to contact mouse skin by topical application for 18 hr.
  • Results are the mean log[LU per cm 2 skin] ⁇ SE (n is shown on top of each column).
  • adenovirus may be inactivated by UV irradiation before complexing with DNA to prevent viable viral particles from disseminating.
  • DNA/adenovirus complexes may appear as the most promising carrier system for the delivery of non-invasive vaccines when efficiency and safety factors are both considered in formulating a new generation of vaccines.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (10)

  1. Verwendung eines adenoviralen Vektors, der für ein Transgen von Interesse zur Herstellung eines non-invasiven Impfstoffes zur Induktion einer Immunreaktion bei einem Tier durch non-invasiven Auftrag des Vektors auf die Tierhaut kodiert.
  2. Verwendung nach Anspruch 1, worin das Transgen für ein Antitumorantigen kodiert und die Immunreaktion eine Antitumorimmunreaktion ist.
  3. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin das Transgen für ein Antigen kodiert.
  4. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin das Antigen gegen ein Pathogen oder Neoplasma verwendet werden kann.
  5. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin das Antigen aus der Gruppe hauptsächlich bestehend aus dem humanen karzinoembryonales Antigen, dem HIV gp120-Antigen und den Influenza-NP-Antigenen ausgewählt ist.
  6. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin der Vektor weiterhin für ein co-anregendes Gen und ein Cytokingen kodiert.
  7. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin das immunregulierende Gen aus der Gruppe bestehend aus einem GM-CSF-Gen, einem B7-1-Gen, einem B7-2-Gen, einem Interleukin-2-Gen und einem Interleukin-12-Gen ausgewählt ist.
  8. Verwendung nach irgendeinem der vorhergehenden Ansprüche, worin der Adenovirusvektor in seiner E1-Region defekt ist.
  9. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin alle viralen Gene des Vektors deletiert werden.
  10. Verwendung nach irgendeinem der vorgehenden Ansprüche, worin der Vektor einen DNA/Viruskomplex umfasst und die DNA in plasmider Form vorliegt.
EP98939363A 1997-08-13 1998-08-13 Impfung durch topische verwendung genetischer vektoren Expired - Lifetime EP1015035B1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US5552097P 1997-08-13 1997-08-13
US55520P 1997-08-13
US7511398P 1998-02-11 1998-02-11
US75113P 1998-02-11
PCT/US1998/016739 WO1999008713A1 (en) 1997-08-13 1998-08-13 Vaccination by topical application of genetic vectors

Publications (3)

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EP1015035A1 EP1015035A1 (de) 2000-07-05
EP1015035A4 EP1015035A4 (de) 2005-06-15
EP1015035B1 true EP1015035B1 (de) 2009-01-28

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EP98939363A Expired - Lifetime EP1015035B1 (de) 1997-08-13 1998-08-13 Impfung durch topische verwendung genetischer vektoren

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EP (1) EP1015035B1 (de)
JP (3) JP2001515052A (de)
KR (2) KR20080009171A (de)
CN (1) CN100352511C (de)
AT (1) ATE421888T1 (de)
AU (1) AU737717B2 (de)
CA (1) CA2301328A1 (de)
DE (1) DE69840524D1 (de)
WO (1) WO1999008713A1 (de)

Cited By (5)

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US9605276B2 (en) 2012-08-24 2017-03-28 Etubics Corporation Replication defective adenovirus vector in vaccination
US10695417B2 (en) 2015-01-09 2020-06-30 Etubics Corporation Human adenovirus serotype 5 vectors containing E1 and E2B deletions encoding the ebola virus glycoprotein
US11149087B2 (en) 2015-04-20 2021-10-19 Etubics Corporation Methods and compositions for combination immunotherapy
US11344613B2 (en) 2007-07-02 2022-05-31 Etubics Corporation Sequential administration of a replication defective adenovirus vector in vaccination protocols
US11352642B2 (en) 2015-01-09 2022-06-07 Etubics Corporation Methods and compositions for combination immunotherapy

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US11344613B2 (en) 2007-07-02 2022-05-31 Etubics Corporation Sequential administration of a replication defective adenovirus vector in vaccination protocols
US11369673B2 (en) 2007-07-02 2022-06-28 Etubics Corporation HPV vaccines and methods of use thereof
US11376316B2 (en) 2007-07-02 2022-07-05 Etubics Corporation Breast cancer vaccines and methods of use thereof
US9605276B2 (en) 2012-08-24 2017-03-28 Etubics Corporation Replication defective adenovirus vector in vaccination
US10563224B2 (en) 2012-08-24 2020-02-18 Etubics Corporation Replication defective adenovirus vector in vaccination
US10695417B2 (en) 2015-01-09 2020-06-30 Etubics Corporation Human adenovirus serotype 5 vectors containing E1 and E2B deletions encoding the ebola virus glycoprotein
US11352642B2 (en) 2015-01-09 2022-06-07 Etubics Corporation Methods and compositions for combination immunotherapy
US11149087B2 (en) 2015-04-20 2021-10-19 Etubics Corporation Methods and compositions for combination immunotherapy

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DE69840524D1 (de) 2009-03-19
AU737717B2 (en) 2001-08-30
WO1999008713A1 (en) 1999-02-25
KR20080009171A (ko) 2008-01-24
CN100352511C (zh) 2007-12-05
AU8780798A (en) 1999-03-08
KR20010022863A (ko) 2001-03-26
CN1274290A (zh) 2000-11-22
CA2301328A1 (en) 1999-02-25
EP1015035A4 (de) 2005-06-15
JP2014101379A (ja) 2014-06-05
EP1015035A1 (de) 2000-07-05
ATE421888T1 (de) 2009-02-15
HK1032753A1 (zh) 2001-08-03
JP2011068658A (ja) 2011-04-07
JP2001515052A (ja) 2001-09-18

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